Synergistic effects of combined lead and iprodione exposure on P53 signaling-mediated hepatotoxicity, enterotoxicity and transgenerational toxicity in zebrafish

Environmental heavy metal contamination, combined with inappropriate use of fungicides, has led to the co-existence of lead (Pb) and iprodione (IPR), presenting signification risks to ecosystems and human health. The toxic effects resulting from concurrent exposure to Pb and IPR, however, remain poorly understood. In the study, we conducted a comprehensive 60-day subchronic study to investigate the toxic effects on the liver and gut in parental male zebrafish through employing multi-omics analyses. We also explored the potential transgenerational toxicity to unexposed offspring embryos. The results demonstrated that exposure to both Pb and IPR exacerbated intestinal pathological damage, decreased the expression of intestinal tight junction molecules, and activated the expression of intestinal inflammatory molecules in the gut. Metabolic and microbial analyses, utilizing 16S rRNA sequencing and non-targeted metabolic profiling, revealed alterations in the intestinal flora structure and disruptions in metabolite synthesis. Notably, we observed a significant negative correlation between the abundance of the Lactobacillus genus and uracil synthesis. Furthermore, liver RNA-seq analysis identified a marked enrichment of the P53 signaling pathway, confirmed by the activation of P53-mediated apoptotic markers, which was consistent with the observed increase in inflammatory infiltration and pathological damage within the liver. Importantly, P53-mediated apoptosis and inflammatory responses were activated in offspring embryos, suggesting that long-term parental exposure to Pb and IPR may induce transgenerational toxicity, potentially impacting offspring health. Despite the identification of these molecular changes, the phenotypic effects remain to be elucidated. Future studies are necessary to evaluate the potential phenotypic changes in offspring to fully understand the long-term effects of Pb and IPR exposure. Overall, these findings enhance the understanding of the molecular mechanisms underlying the toxic effects of Pb and IPR and emphasize the importance of a comprehensive risk assessment of environmental pollutants. [Display omitted] •Exposure to lead and iprodione significantly damaged intestinal health of zebrafish.•Microbiota and metabolic functions are markedly altered in the intestine.•P53 signaling pathway and P53-mediated apoptotic molecules were activated in the liver.•Genetic impacts were observed across generations.•The co-existence of lead and iprod